Bench‐Stable Electrophilic Indole and Pyrrole Reagents: Serendipitous Discovery and Use in C–H Functionalization

The development of reagents allowing the reversal of the standard reactivity (Umpolung) of small building blocks is an important field of research in chemistry, as it allows increasing the flexibility of organic synthesis. Indoles and pyrroles are ubiquitous heterocycles in natural products and drugs. They are usually functionalized making use of their high nucleophilicity. In contrast, only few methods are based on the use of electrophilic indole and pyrrole synthons, as the needed reagents are highly unstable or can be used only with a very narrow scope. Herein, we report the serendipitous discovery and first use in the C–H functionalization of arenes of IndoleBX and PyrroleBX, new thermally highly stable benziodoxol(on)e hypervalent iodine reagents. IndoleBX and PyrroleBX could be obtained in one step from the corresponding heterocycles and acetoxy benziodoxolone using a Lewis acid catalyst. The mild reactions conditions allowed the introduction of a broad range of functional groups, including ethers, halogens and boronic esters. The new reagents could then be used in the rhodium‐ and ruthenium‐catalyzed C–H heteroarylation of arene rings bearing heterocyclic or benzamide directing groups. Such transformations could not be realized using previously reported C–H functionalization procedures.     

Computational I(III)—X BDEs for Benziodoxol(on)e‐based Hypervalent Iodine Reagents: Implications for Their Functional Group Transfer Abilities

The first comprehensive I(III)―X (X = F, Br, CN, N₃, CF₃, etc.) bond dissociation energy (BDE) scales for benziodoxol(on)e‐based hypervalent iodine reagents have been developed by virtue of DFT calculations. Excellent correlation is observed between the I(III)―X BDEs and the X―H BDEs, offering a powerful avenue to quickly estimate the group‐transfer ability of a novel benziodoxol(on)e‐based hypervalent reagent.     

Synthetic approaches for BF2-containing adducts of outstanding biological potential. A review

Organic compounds containing the F or B elements in their structures have recently attracted the interest of the chemists and medicinal chemists because their improved biological properties displayed in comparison to their non-fluorinated or non-borinated parent structures. It is widely been documented that curcumine (CUR) have a high biological potential as antioxidant, anti-inflammatory and anticancer agent, among others, but some drawbacks related to its unfavorable bio-physicochemical properties have prevented its applicability as chemotherapeutic drug. Nevertheless, recent studies have shown that the introduction of the BF₂ functionality in its structure (i.e. CUR-BF₂ adducts) and analogues have significantly improved their biological properties, mainly, their anticancer and antibiotic activities.On the other hand, the BF₂-adduct BODIPY (i.e. 4,4-difluoro-4-bora-3a-azonia-4a-aza-s-indacene) and derivatives are widely known by their outstanding photophysical properties displayed. However, recently it have increased the interest in such structures, but this time, for the biological properties that these fluorescent compounds are also shown, as convenient probes for diverse biological targets.Focusing on the above findings, we were interested into compile, in this review article, the literature documented since 2000–2020 exclusively engaged with the synthetic strategies established for the synthesis of curcumine-BF₂ adducts, BODIPY and their related derivatives, in which the biological properties displayed by such structures have been highlighted. Remarkably, the biological activities displayed by the aforementioned BF₂-based compounds are mainly related with cell imaging studies, biomolecules recognition and labels, antibiotic properties and antiproliferative agents, which were conveniently used to organize them in concise Tables and Schemes to facilitate their comparisons, and to underscore the key points of the present review.     

Regio- and Stereoselective Syntheses with Organocopper Reagents

Of all of the organometallic reagents currently used to form carbon–carbon bonds, organocopper reagents rank amongst the most important. Interest in these reagents centers not only on their regioselectivity, but also increasingly on their application in stereoselective transformations (principally Michael additions and S_N2′ reactions); the use of suitable substrates or chirally modified cuprates can lead to highly diastereo- and enantioselective reactions. Simultaneously, extensions of methods for the preparation and application of these reagents (for example functionalized organocopper species and Lewis acid catalysis, respectively) have opened up new horizons for organocopper reagents. Mechanistically, the reactions are well-documented and understood, but this aspect of the subject has not kept pace with the many rapid developments in preparative chemistry. Organocopper ragents have proved to be indispensable in the synthesis of complex natural products and pharmaceuticals, chiral auxiliaries, and molecules with interesting structural features. In this review we will discuss some of the more recent important developments in this area; the organization will follow the type of selectivity (regio-, diastereo-, and enantioselectivity).     

Enantiomeric impurities in chiral catalysts,auxiliaries, and synthons used in enantioselective syntheses. Part 4

The enantiomeric purity of chiral reagents used in asymmetric syntheses directly affects the apparent reaction selectivity and the product’s enantiomeric excess. Herein, 46 recently available chiral compounds were evaluated in order to determine their actual enantiomeric compositions. They have not been assayed previously and/or have been introduced after 2006, when the last comprehensive evaluation of commercially available chiral compounds was reported. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. The enantioselective analysis methods include HPLC approaches using Chirobiotic, Cyclobond and LARIHC series chiral stationary phases, and GC approaches using Chiraldex chiral stationary phases. Accurate, efficient assays for selected compounds are given. All enantiomeric test results were categorized within five impurity levels (i.e., <0.01%, 0.01–0.1%, 0.1–1%, 1–10% and >10%). Different batches of the same reagent from the same company can have different levels of enantiomeric impurities. Many of the reagents tested were found to have less than 0.1% enantiomeric impurities. Only one of the chiral compounds was found to have an enantiomeric impurity exceeding 10%.     

Di-Grignard Compounds and Metallacycles

Just as the by now famous Grignard reaction can be used to prepare organomagnesium halides from organic monohalides, organic dihalides can be used under certain conditions to prepare di-Grignard compounds. Difficulties are encountered in particular when the two halide functionalities are separated by only a short carbon chain (i. e. by 1-3 carbon atoms): in such cases side reactions predominate. It has however recently become possible to obtain such “short” di-Grignard compounds on a preparatively useful scale. This opens up new perspectives for the synthesis of metallacyclic compounds of other main group and transition metal elements and in particular for metallacyclobutanes. The preparation, structure and application of a selected number of di-Grignard reagents will be treated in the present review.     

Organometall‐Reaktionen in Wasser

Water has attracted significant attention as an alternative solvent for organometallic reactions because it is nontoxic, nonflammable, and inexpensive, and is easily separated from organic products. Organometallic reactions, like the palladium‐catalyzed couplings of organic halides with organoboron compounds (Suzuki) and organotin reagents (Stille), are among the most widely used reactions for the formation of carbon‐carbon bonds. Owing to the discovery of water‐soluble, sulfonated phosphane derivatives and particularly the design of water‐soluble palladium‐catalysts it was possible to import these reactions into aqueous media. Another efficient, metal‐catalyzed, carbon‐carbon bond‐forming process that is nowadays possible in aqueous media is the olefin metathesis. The approaches so far include the use of water‐soluble ruthenium‐catalysts, surfactants and additives, ultrasonication, the introduction of polar quaternary ammonium groups or the incorporation of PEG as a water solubilizing moiety. The last point bears also a great potential for further developments in the removal of ruthenium‐containing byproducts. Additionally, water is the ideal reaction environment for polar, water soluble substrates such as natural product or pharmaceuticals.     

The structures of lithium and magnesium organocuprates and related species

Organocuprates are excellent reagents for the formation of carbon–carbon bonds and have been used extensively in synthetic methodology for over fifty years. However, despite their long pedigree the structures, solution behavior, and mechanism of operation of these reagents have often remained opaque. This review concentrates upon the resting-state structures of organocuprates as determined using X-ray crystallographic studies, and provides a comprehensive survey of all solid-state structural characterizations of these species and the intricate nature of their supramolecular assemblies. In addition, solution state experimental data is also presented where it pertains directly to the presented solid-state structures or where it illustrates key points crucial to the understanding of organocuprate reactivity. The structures of all the main classes of organocuprate reagent will be discussed including lithium and magnesium homo-cuprates, cyano-cuprates and hetero-cuprates.     

Microbial Degradation of Halogenated Hydrocarbons: A Biological Solution to Pollution Problems?

Chlorinated hydrocarbons are widely used because of their chemical and thermal stability as well as their fungicidal, herbicidal, and insecticidal properties. Unfortunately, it is just this stability that makes the compounds persistent in nature; half-lives of more than 15 years are not uncommon. In many countries the use of some chlorinated compounds has been prohibited, even though many such compounds (e.g., DDT) exhibit exactly the desired spectrum of effects. Surprisingly, microbiol systems that can degrade most chlorinated hydrocarbons have been found in nature. Indeed, it is possible, in many cases, to isolate pure cultures of bacteria that can utilize these compounds as the sole source of carbon and energy. Even polychlorinated compounds, such as the wood preservative and herbicide pentachlorophenol, can be utilized as a source of carbon by some bacteria. The study of the biodegradation of halogenated hydrocarbons has led to the discovery of novel catabolic pathways in which unusual and previously undescribed enzymatic activities have been detected. Bacterial enzymes have even been isolated that can replace halogen substituents in aliphatic and aromatic compounds with hydroxyl groups or hydrogen atoms. Improved understanding of the biodegradation of halogenated hydrocarbons, as described in this article, will almost certainly result in new biotechnological applications, especially in the area of waste-water treatment.     

Fischer carbene complexes: beautiful playgrounds to study single electron transfer (SET) reactions

The knowledge of the reactivity of Fischer carbene complexes in electron transfer processes is still in the early stage of development, but interesting advances are foreseeable in this young branch of metal-carbene chemistry. Although these compounds have a dual reactivity (which makes them good substrates for oxidation and reduction processes), their behavior towards chemical electron transfer (ET) reagents was unknown until very recently. This article covers the progress accomplished in the reactivity of these compounds towards chemical ET reagents (C(8)K or SmI(2)), as well as the use of nonconventional sources of electrons, such as electrospray ionization (ESI) to induce ET processes. Special emphasis will be made on the effect of the structure of the starting carbene in the outcome of the reaction and in discussing the different mechanisms proposed.     

Transition Metals in the Synthesis and Functionalization of Indoles [New Synthesis Methods (72)]

The use of transition-metal complexes as reagents for the synthesis of complex organic compounds has been under development for at least several decades, and many extraordinary organic transformations of profound potential have been realized. However, adoption of this chemistry by the practicing synthetic organic chemist has been inordinately slow, and only now are transition-metal reagents beginning to achieve their rightful place in the arsenal of organic synthesis. Several factors contributed to the initial reluctance of synthetic organic chemists to use organometallic reagents. Lacking education and experience in the ways of elements having d electrons, synthetic chemists viewed organometallic processes as something mysterious and unpredictable, and not to be discussed in polite society. Organometallic chemists did not help matters by advertising their latest advances as useful synthetic methodology, but restricting their studies to very simple organic systems lacking any serious functionality (e.g., the “methyl, ethyl, butyl, futile” syndrome). Happily, things have changed. Organometallic chemists have turned their attention to more complex systems, and more recently trained organic chemists have benefited from exposure to the application of transition metals. This combination has set the stage for major advances in the use of transition metals in the synthesis of complex organic compounds. This review deals with one aspect of this area, the use of transition metals in the synthesis of indoles.     

Enantiomeric impurities in chiral synthons,catalysts, and auxiliaries: Part 3

The enantiomeric excess of chiral reagents used in asymmetric syntheses directly affects the reaction selectivity and product purity. In this work, 84 of the more recently available chiral compounds were evaluated to determine their actual enantiomeric composition. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. These include chiral alcohols, amines, amino alcohols, amides, carboxylic acids, epoxides, esters, ketones, and oxolanes among other classes of compounds. All enantiomeric test results were categorized within five impurity levels (i.e., <0.01%, 0.01–0.1%, 0.1–1%, 1–10%, and >10%). The majority of the reagents tested were determined to have enantiomeric impurities over 0.01%, and two of them were found to contain enantiomeric impurities exceeding the 10% level. The most effective enantioselective analysis method was a GC approach using a Chiraldex GTA chiral stationary phase (CSP). This method worked exceedingly well with chiral amines and alcohols.     

Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl

A series of new hypervalent iodine reagents based on the 1,3‐dihydro‐3,3‐dimethyl‐1,2‐benziodoxole and 1,2‐benziodoxol‐3‐(1H)‐one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon‐centered nucleophiles afford products that feature a tetrafluoroethylene unit, which connects two functional moieties. A related λ³‐iodane that contains a fluorophore was shown to react with a cysteine derivative under mild conditions to give a thiol‐tagged product that is stable in the presence of excess thiol. Therefore, these new reagents show a significant potential for applications in chemical biology as tools for fast, irreversible, and selective thiol bioconjugation.     

New Catalytic Approaches towards the Enantioselective Halogenation of Alkenes

The addition of electrophilic reagents to the carbon–carbon double bond is one of the most fundamental reactions in organic chemistry. Halogen electrophiles constitute probably the most important class of electrophiles and have been widely used to induce electrophilic addition reactions to alkenes like halolactonizations or dihalogenations. Despite their long history and high importance, catalytic, asymmetric variants of these reactions have been underdeveloped until very recently. During the last two years this has changed and many novel approaches have been reported. This review aims to cover these new developments through discussing the common themes as well as the suggested mechanistic scenarios.     

Graphene oxide supported tin dioxide: synthetic approaches and electrochemical characterization as anodes for lithium- and sodium-ion batteries

The review addresses synthetic approaches to composite materials based on graphene oxide and nano tin dioxide and their electrochemical properties as anodes for lithium- and sodiumion batteries. The introduction of a carbon matrix into the composite material improves the electrochemical characteristics of the anodes. In most methods, the synthesis of graphene oxide–tin dioxide composites is based on the use of tin(II,IV) chlorides as the starting compounds, and the most efficient electrode materials were obtained by the hydrothermal or solvothermal routes. Thermal processing is much more economic than the gas phase deposition protocols but requires heating of a large volume of dilute tin oxide dispersions in an autoclave. Mechanochemistry (ball milling) is also economically unfavorable for the synthesis of composite materials. In addition, large volumes of acidic wastes that should be neutralized and safely discarded are formed when tin chlorides are used. An alternative environmentally friendly technique based on the use of aqueous peroxide solutions can be applied for the production of efficient anode materials based on graphene oxide and tin dioxide. This process does not involve acidic wastes, uses hydrogen peroxide and ethanol as reagents, and accomplishes film deposition (coating) at room temperature. Final thermal treatment is required only for the active material, which minimizes energy expenses and equipment costs.     

Recyclable catalysts for the synthesis of heterocyclic compounds using carbon materials

Heterogeneous catalytic reactions play a major role in the industry to produce a number of compounds that are essential in our daily life. Synthesis of heterocyclic compounds using heterogeneous catalysis is one of the rapidly growing research areas. Inherent ability to produce high selectivity and potentiality to recycle, the catalyst makes the heterogeneous systems more attractive, especially on the industrial scale. Various recyclable catalytic systems have been extensively developed for the synthesis of heterocyclic compounds via dehydration, partial oxidations, three-component couplings, dehydrogenations, and others. Different supports like polymers, metal oxides, and quite recently carbon supports like carbon nanotubes (CNTs), graphene oxide (GO), graphitic nitride (GCN), and nitrogenous carbon materials (NGr) have been widely used to synthesize diverse heterocycles. The use of GO in the synthesis of heterocyclic compounds has been reviewed recently, hence we did not focus on GO in this review. The aim of this review article is to explore the emerging areas of carbon-based heterogeneous materials such as CNTs, GCN, and NGr in the synthesis of heterocycles. This review also focused on the most recent examples, their preparation, and recycling studies of highly excited catalytic systems used for the heterocycles.     

Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents

Electrophilic trifluoromethylation reactions have been the latest approach to achieve the fluoroalkylation of compounds with newly‐discovered reagents, such as the Togni’s (1‐trifluoromethyl‐1,2‐benziodoxol‐3‐(1 H)‐one), Umemoto’s (S‐(trifluoromethyl)dibenzothiophenium tetrafluoroborate), Yagupolskii’s (S‐(trifluoromethyldiarylsulfonium salts), Shreeve’s (S‐(trifluoromethyl)dibenzothiophenium triflate), and Shibata’s (trifluoromethylsulfoximine salts) reagents. All these reagents produce an electrophilic trifluoromethylating (CF₃⁺) species that undergoes reaction with nucleophiles. In addition, these latter reactive species (i.e. CF₃⁺) can undergo electron‐transfer (ET) processes affording CF₃ ^? radicals that expand the scope to substrates other than conventional nucleophiles that can undergo reaction. In this Review, we shall discuss the trifluoromethylation reactions of diverse families of organic substrates of biological interest as a means to comparing the reagents scope and best reaction conditions. Some, though not all, of these reactions require the assistance of metal or organometallic catalysts. Some require additives and catalysts to promote the fluoroalkylation reaction, but invariably all are initiated and carried out by electrophilic trifluoromethylating species.     

Organic synthesis using chemical tags: the third Leg of parallel synthesis

Increasing emphasis has recently been placed on the development of synthetic methods which effectively couple chemical synthesis and purification. For example, new formats for parallel synthesis are being developed which involve attachment of chemical tags to both reagents, reactants, and substrates to permit their chemoselective removal from reaction mixtures. The driving force for the development of tagged organic reagents is the ability to use standard solution-phase chemistry methods and reaction monitoring techniques (e.g. TLC and HPLC). In this mini-review, we will outline recent developments on the growing class of chemically tagged reagents, reactants, and substrates and highlight examples of their use in multistep synthesis.     

Radical‐Induced Metal‐Free Alkynylation of Aldehydes by Direct CH Activation

A direct C(sp²)?H alkynylation of aldehyde C(O)?H bonds with hypervalent iodine alkynylation reagents provides ynones under metal‐free conditions. In this method, 1‐[(triisopropylsilyl)ethynyl]‐1,2‐benziodoxol‐3(1H)‐one (TIPS‐EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and α,β‐unsaturated aldehydes.     

Lipid analysis by thin-layer chromatography--a review of the current state

High-performance thin-layer chromatography (HPTLC) is a widely used, fast and relatively inexpensive method of separating complex mixtures. It is particularly useful for smaller, apolar compounds and offers some advantages over HPLC. This review gives an overview about the special features as well as the problems that have to be considered upon the HPTLC analysis of lipids. The term "lipids" is used here in a broad sense and comprises fatty acids and their derivatives as well as substances related biosynthetically or functionally to these compounds. After a short introduction regarding the stationary phases and the methods how lipids can be visualized on an HPTLC plate, the individual lipid classes will be discussed and the most suitable solvent systems for their separation indicated. The focus will be on lipids that are most abundant in biological systems, i.e. cholesterol and its derivates, glycerides, sphingo- and glycolipids as well as phospholipids. Finally, a nowadays very important topic, the combination between HPTLC and mass spectrometric (MS) detection methods will be discussed. It will be shown that this is a very powerful method to investigate the identities of the HPTLC spots in more detail than by the use of common staining methods. Future aspects of HPTLC in the lipid field will be also discussed.